Visceral pain is a leading cause of patient visits to the clinic, yet effective treatments for visceral pain are limited. Visceral pain is difficult to manage clinically and often requires the use of opiates. Although widely used, the severe dose-limiting adverse effects of opiates often result in diminished efficacy. Additionally, opiates carry the risk of abuse and physical dependence and induce constipation and other unwanted adverse effects, which are contraindicated in many cases and diminish quality of life.
Visceral pain is pain associated with the viscera, which encompass the internal organs of the body. These organs include, e.g., the heart, lungs, reproductive organs, bladder, ureters, the digestive organs, liver, pancreas, spleen, and kidneys. There are a variety of conditions in which visceral pain may exist, such as, for example, pancreatitis, labor, abdominal surgery associated with ileus, cystitis, menstrual period, or dysmenorrhea. Likewise, kidney pain, epigastric pain, pleural pain, and painful biliary colic, appendicitis pain may all be considered to be visceral pain. Substernal pain or pressure from early myocardial infarction is also visceral. Diseases of the stomach, duodenum or colon can cause visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause visceral pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, with respect to FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, with respect to IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
IBS affects 10-20% of adults and adolescents worldwide (Longstreth et al., 2006, Gastroenterology 130(5):1480-91). The primary reason these patients seek medical attention is chronic visceral pain believed to be due to enhanced visceral sensitivity (Aziz, 2006, Gastroenterology 131(2):661-4). Patients with IBS have been shown to have a lower visceral sensory threshold to colorectal distension and that this is highly correlated to the visceral pain symptoms (Delafoy et al, 2006, Gut 55(7):940-5). Colorectal distension after trinitrobenzene sulfonic acid (TNBS) induced colitis in rats is an animal model that has been used by many researchers to explore the mechanisms of visceral hypersensitivity (Gay et al, 2006, Neuroimmunomodulation 23; 13(2):114-121; Delafoy et al, 2006; Adam et al., 2006, Pain 123(1-2):179-86).
Interstitial cystitis (IC) is a painful bladder syndrome characterized in the clinic by urinary urgency, frequency and chronic pelvic pain. Clinical studies indicate that this involves visceral sensory afferent nerve hypersensitivity where the sensation of bladder fullness occurs at lower than patients indicates an increase in nerve density in the submucosa of the bladder and evidence of neurogenic inflammation further normal volumes and bladder fullness is perceived as painful. Histopathology of IC suggests the involvement of visceral afferents.
Visceral pain can be produced in response to, for example, inflammation, distention, or increased pressure. It is not always elicited by visceral injury. In addition, visceral pain is diffuse, may be referred to other locations; and may be associated with other autonomic and motor reflexes (e.g., nausea, lower-back muscle tension from renal colic) (Lancet 1999, 353, 2145-48).
CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide, which belongs to a family of peptides that includes calcitonin, adrenomedullin and amylin. In humans, two forms of CGRP (α-CGRP and β-CGRP) exist and have similar activities. They vary by three amino acids and exhibit differential distribution. At least two CGRP receptor subtypes may also account for differential activities. CGRP is a neurotransmitter in the central nervous system, and has been shown to be a potent vasodilator in the periphery, where CGRP-containing neuronal processes are closely associated with blood vessels. CGRP-mediated vasodilatation is also associated with neurogenic inflammation, as part of a cascade of events that results in extravasation of plasma and vasodilation of the microvasculature and is present in migraine.
Spinally administered small molecule selective CGRP antagonists have been shown to be useful in the treatment of neuropathic and nociceptive pain conditions (Adwanikar et al, Pain, 2007, 132(1-2):53-66) suggesting that removal of endogenous CGRP signalling in the spinal cord has an antinociceptive effect. Reports have established that blocking CGRP signalling is effective in reversing visceral hypersensitivity (VH) by systemically injecting CGRP 8-37, a CGRP receptor antagonist (Delafoy et al., 2006; Plourde et al., 1997, Am J. Physiol. 273(1 Pt 1):G191-6; Julia and Bueno, 1997, Am J. Physiol. 272(1 Pt 1):G141-6). However, CGRP 8-37 has a very short half-life in-vivo and would therefore not be a useful therapeutic. Thus, there is a critical medical need to identify new therapeutics for the treatment and prevention of visceral pain.
Throughout this application various publications (including patents and patent applications) are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference.